Phase 3 Trial Enrollment, Topline Data Expected Earlier for Pitolisant in Idiopathic Hypersomnia

Jeffrey Dayno, MD

According to a recent announcement, the timeline for the phase 3 INTUNE study (NCT05156047) assessing Harmony’s therapy pitolisant (Wakix) in patients with idiopathic hypersomnia (IH) has been accelerated, with enrollment expected to be complete by the second quarter of 2023 and topline data anticipated to be read out in the fourth quarter of this year.

Based on a pre-specified interim sample size analysis, a recently convened independent data monitoring committee concluded that the study could continue with the original planned enrollment population. INTUNE, a double-blind, placebo-controlled, randomized, withdrawal study, spans 60 sites in the US, and includes approximately 200 patients with IH. The study, announced in April 2022, uses change in Epworth Sleepiness Scale (ESS) score as the primary outcome measure to assess the effects of pitolisant vs placebo.

"The strong interest we have seen from the IH patient community and our clinical investigators in this trial is indicative of the true unmet medical need for a non-scheduled, once-daily treatment option working through histamine to improve wakefulness for people living with IH," Jeffrey Dayno, MD, interim chief executive officer and chief medical officer, Harmony Biosciences, said in a statement.¹ "The momentum in this trial, as well as the growth of WAKIX in narcolepsy, reflects the positive experience of patients and the confidence of prescribers in this meaningfully differentiated product. Furthermore, we are confident in the strength of our underlying business and our ability to execute on our three-pillar growth strategy."

Pitolisant, a selective histamine 3 receptor antagonist/inverse agonist, remains the only FDA-approved treatment for both excessive daytime sleepiness and cataplexy in narcolepsy that is not a scheduled controlled substance. It first gained FDA greenlight for EDS in 2019 and later for cataplexy in the following year. For years, IH had been treated with off-label agents until 2021, when the FDA approved JZP-258 (Xywav; Jazz Pharmaceuticals), a combination agent of calcium, magnesium, potassium, and sodium oxybates, as the first therapeutic specific for this condition.

READ MORE: Mazindol Extended Release Agent Demonstrates Significant Efficacy in Open-Label Extension in Narcolepsy

In addition to change in ESS, the study will also look at other secondary outcomes such as impact on symptoms of inertia and cognitive impairment. Other outcomes, including patient impression of overall change in symptoms, investigator assessment of overall disease activity, and functional status, will also be evaluated in the study. These assessments will be measured via the Patient Global Impression of Change and Severity scales, the functional outcomes of the Sleep Questionnaire 10-item version, the Sleep Inertia Questionnaire, and the Cogstate One Back Test, among others.

The study consists of a screening period for up to 28 days, an 8-week open-label phase, and a 4-week double-blind randomized withdrawal phase. The open-label phase of the study comprises of a 6-week dose optimization period in which all patients will be titrated to an optimal dose of either 17.8 mg or 35.6 mg, and 2-week stable dose period. The 3-week titration period will be followed by 3 weeks of flexible dosing during which patients will continue to receive their optimal dose of 17.8 mg or 35.6 mg open-label pitolisant.

Patients in the study are all at least 18 years old, had an ESS score of at least 12 at screening and at baseline, had a PGI-S score of moderate, severe, or very severe, and had a diagnosis of IH based on International Classification Sleep Disorders Third Edition criteria. For patients being treated for obstructive sleep apnea or other hypoventilatory conditions, patients must be compliant as demonstrated by BiPAP/CPAP therapy with 30 days of data showing at least 4 hours of therapy per night for at least 70% of the nights. Patients on treatment that could impact daytime sleepiness—such as oxybates, stimulants, modafinil, and armodafinil—must be on a stable dose for at least 2 months prior to screening, or if not, washout for 5 half-lives or 14 days.

REFERENCES
1. Harmony Biosciences announces accelerated timeline for phase 3 INTUNE study in idiopathic hypersomnia. News release. March 29, 2023. Accessed April 3, 2023. https://www.prnewswire.com/news-releases/harmony-biosciences-announces-accelerated-timeline-for-phase-3-intune-study-in-idiopathic-hypersomnia-301784513.html
2. Harmony Biosciences initiates phase 3 trial of pitolisant in adult patients with idiopathic hypersomnia. News release. Harmony Biosciences. April 27, 2022. Accessed April 3, 2023. https://www.harmonybiosciences.com/newsroom/harmony-biosciences-initiates-phase-3-trial-of-pitolisant-in-adult-patients/